rs75568433

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_182914.3(SYNE2):​c.14197C>A​(p.Pro4733Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,614,150 control chromosomes in the GnomAD database, including 227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 8 hom., cov: 32)
Exomes 𝑓: 0.015 ( 219 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

7
11

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.78
Variant links:
Genes affected
SYNE2 (HGNC:17084): (spectrin repeat containing nuclear envelope protein 2) The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]
ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.005111128).
BP6
Variant 14-64130105-C-A is Benign according to our data. Variant chr14-64130105-C-A is described in ClinVar as [Benign]. Clinvar id is 313597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64130105-C-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0102 (1552/152306) while in subpopulation NFE AF= 0.0172 (1168/68024). AF 95% confidence interval is 0.0164. There are 8 homozygotes in gnomad4. There are 699 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 1552 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SYNE2NM_182914.3 linkuse as main transcriptc.14197C>A p.Pro4733Thr missense_variant 76/116 ENST00000555002.6 NP_878918.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SYNE2ENST00000555002.6 linkuse as main transcriptc.14197C>A p.Pro4733Thr missense_variant 76/1161 NM_182914.3 ENSP00000450831.2 Q8WXH0-2A0A0C4DGK3

Frequencies

GnomAD3 genomes
AF:
0.0102
AC:
1555
AN:
152188
Hom.:
9
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00314
Gnomad AMI
AF:
0.0208
Gnomad AMR
AF:
0.00739
Gnomad ASJ
AF:
0.0167
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.000830
Gnomad FIN
AF:
0.00330
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0172
Gnomad OTH
AF:
0.0124
GnomAD3 exomes
AF:
0.00975
AC:
2446
AN:
250990
Hom.:
26
AF XY:
0.00945
AC XY:
1282
AN XY:
135640
show subpopulations
Gnomad AFR exome
AF:
0.00265
Gnomad AMR exome
AF:
0.00581
Gnomad ASJ exome
AF:
0.0180
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00219
Gnomad FIN exome
AF:
0.00407
Gnomad NFE exome
AF:
0.0158
Gnomad OTH exome
AF:
0.0116
GnomAD4 exome
AF:
0.0154
AC:
22445
AN:
1461844
Hom.:
219
Cov.:
32
AF XY:
0.0150
AC XY:
10907
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00242
Gnomad4 AMR exome
AF:
0.00624
Gnomad4 ASJ exome
AF:
0.0164
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00211
Gnomad4 FIN exome
AF:
0.00446
Gnomad4 NFE exome
AF:
0.0184
Gnomad4 OTH exome
AF:
0.0133
GnomAD4 genome
AF:
0.0102
AC:
1552
AN:
152306
Hom.:
8
Cov.:
32
AF XY:
0.00939
AC XY:
699
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.00308
Gnomad4 AMR
AF:
0.00738
Gnomad4 ASJ
AF:
0.0167
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000623
Gnomad4 FIN
AF:
0.00330
Gnomad4 NFE
AF:
0.0172
Gnomad4 OTH
AF:
0.0123
Alfa
AF:
0.0154
Hom.:
32
Bravo
AF:
0.0106
TwinsUK
AF:
0.0170
AC:
63
ALSPAC
AF:
0.0215
AC:
83
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.0198
AC:
170
ExAC
AF:
0.00966
AC:
1173
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.0141
EpiControl
AF:
0.0167

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsOct 15, 2020- -
not provided Benign:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.090
CADD
Benign
20
DANN
Benign
0.73
DEOGEN2
Benign
0.029
.;T;T;T;T
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.92
D;D;D;D;D
MetaRNN
Benign
0.0051
T;T;T;T;T
MetaSVM
Benign
-0.75
T
MutationAssessor
Uncertain
2.1
M;.;M;.;.
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-2.7
D;.;D;D;D
REVEL
Benign
0.15
Sift
Benign
0.11
T;.;T;T;T
Sift4G
Uncertain
0.0050
D;D;D;D;D
Polyphen
1.0
D;.;D;.;.
Vest4
0.61
MVP
0.51
MPC
0.34
ClinPred
0.022
T
GERP RS
5.8
Varity_R
0.14
gMVP
0.15

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs75568433; hg19: chr14-64596823; COSMIC: COSV100648735; API